Biochemical mode of action and enantiomeric selectivity of SDZ 89-485, a new triazole antimycotic.
SDZ 89-485, a new triazole antimycotic agent, potently inhibited ergosterol biosynthesis in cells of Candida. Trichophyton and Aspergillus. Biosynthesis was measured both by incorporation of radiolabelled acetate and also by methylation of the sterol side chain. Inhibition was accompanied by accumulation of radiolabel in 4,4-dimethylsterols and to a lesser extent in the 4-methylsterols, consistent with inhibition of lanosterol 14-demethylation. No other steps were affected. Ergosterol biosynthesis in the mycelial growth form of Candida albicans was about twice as sensitive to the drug as that in the yeast form. Inhibition by SDZ 89-485 was qualitatively and quantitatively similar to that shown by other systemically active azoles (ketoconazole, itraconazole, ICI 195,739) in Candida cells and cell-free preparations. Rat liver cell-free cholesterol biosynthesis was much less sensitive to inhibition by SDZ 89-485 than was the equivalent Candida system (selectivity ratio of about 300). In contrast to miconazole and econazole, SDZ 89-485 had no uncoupling effect on respiration in C. albicans cells. The structure of SDZ 89-485 contains an asymmetric centre, the drug being the (-)(R) enantiomer. The (+)(S) enantiomer 89-486, which is antifungally much less effective, was at least 10-fold less active than SDZ 89-485 as an ergosterol biosynthesis inhibitor in all test systems employed. The difference between the two enantiomers appears to reside in stereo-selectivity at the level of interaction with the demethylase enzyme.
Ryder
N S
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Sandoz Forschungsinstitut, Vienna, Austria.
D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000378:metabolism; D001345:Autoradiography; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004875:Ergosterol / Q000096:biosynthesis; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014249:Trichophyton / Q000187:drug effects* / Q000378:metabolism
D000935:Antifungal Agents; D014230:Triazoles; C060176:SDZ 89-485; D002784:Cholesterol; D004875:Ergosterol